This project addresses fundamental issues regarding the synthesis and biological activity of naturally occurring tetrapyrroles. Phytochrome (Pr) is a linear tetrapyrrole that serves as the "on-off" switch in photomorphogenesis. Its mode of action remains unclear. Employing recombinant DNA techniques, together with total synthesis, it is possible to prepare specifically 13c-labelled native Pr (*). Raman spectroscopy will be used to probe configuration and conformation changes during photoactivation of Pr. A number of synthetic phytochromobilin analogs will be reincorporated with the apoprotein C to probe the Pr binding pocket. New methodology will be applied to the synthesis and study of biologically active tetrapyrroles of the chlorin, bacteriochlorin and corrin class. Certain of these compounds show considerable promise in tumor photodynamic therapy, the process by which malignant tissue can be selectively destroyed by site-specific generation of singlet oxygen. In addition, bacteriochlorins of the tolyporphin class inhibit "multi-drug resistance," a common problem in cancer chemotherapy. Cobyric acid is the tetrapyrrole nucleus of vitamin B 12. Practical syntheses of these materials, and analogs, are currently not available.